title: The prometastatic ribosomal S6 kinase 2-cAMP response element-binding protein (RSK2-CREB) signaling pathway up-regulates the actin-binding protein fascin-1 to promote tumor metastasis.
abstract: Metastasis is the leading cause of death in patients with breast, lung, and head and neck cancers. However, the molecular mechanisms underlying metastases in these cancers remain unclear. We found that the p90 ribosomal S6 kinase 2 (RSK2)-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells, leading to up-regulation of a CREB transcription target Fascin-1. We also observed that the protein expression patterns of RSK2 and Fascin-1 correlate in primary human tumor tissue samples from head and neck squamous cell carcinoma patients. Moreover, knockdown of RSK2 disrupts filopodia formation and bundling in highly invasive cancer cells, leading to attenuated cancer cell invasion in vitro and tumor metastasis in vivo, whereas expression of Fascin-1 significantly rescues these phenotypes. Furthermore, targeting RSK2 with the small molecule RSK inhibitor FMK-MEA effectively attenuated the invasive and metastatic potential of cancer cells in vitro and in vivo, respectively. Taken together, our findings for the first time link RSK2-CREB signaling to filopodia formation and bundling through the up-regulation of Fascin-1, providing a proinvasive and prometastatic advantage to human cancers. Therefore, protein effectors of the RSK2-CREB-Fascin-1 pathway represent promising biomarkers and therapeutic targets in the clinical prognosis and treatment of metastatic human cancers.
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Lingtao
authors.initials: L
authors.lastname: Jin
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Gina N
authors.initials: GN
authors.lastname: Alesi
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Young-Mee
authors.initials: YM
authors.lastname: Kim
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Seo
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Cell Signaling Technology, Inc., Danvers, Massachusetts 01923.
authors.forename: Meghan
authors.initials: M
authors.lastname: Tucker
authors.affiliation: Cell Signaling Technology, Inc., Danvers, Massachusetts 01923.
authors.forename: Ting-Lei
authors.initials: TL
authors.lastname: Gu
authors.affiliation: the Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.affiliation: the Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California 94107.
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
authors.affiliation: the Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Magliocca
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Zhuo G
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322,. Electronic address: smkang@emory.edu.
authors.forename: Sumin
authors.initials: S
authors.lastname: Kang
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000096:biosynthesis* / Q000235:genetics; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C502658:FSCN1 protein, human; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3
keywords: Cell Invasion; Cell Migration; Fascin-1; Filopodia; Metastasis; Ribosomal S6 Kinase 2; Serine Threonine Protein Kinase; Signal Transduction; cAMP Response Element-binding